The aim of the previous award was to test the hypothesis that sympathetic nervous system (SNS) activity increases with age at rest and during stress in humans. Neurophysiological and neurochemical approaches were combined to study regional and average whole-body SNS activity as comprehensively as possible. The key positive findings were: a) muscle sympathetic nerve activity (MSNA) and cardiac plasma norepinephrine (PNE) spillover rate (reflecting SNS tone to the heart) increased markedly with age, but renal PNE spillover rate did not; b) total PNE spillover rate (average whole- body SNS tone) was marginally increased with age; and c) highly physically active older adults demonstrated greater levels of MSNA at rest than their sedentary peers. Accordingly, the experimental goals of this amended competitive renewal application will be to investigate the mechanisms responsible for these increases in region-specific and average whole body SNS tone with aging, and to further explore the effect of regular endurance exercise on MSNA. The initial four specific aims of the proposal will be to determine if the age-related increases in SNS tone are associated with: l) elevated cerebral sympathoexcitatory noradrenergic neuronal activity, as indicated by increased internal jugular vein spillover rates of norepinephrine and its metabolites; 2) impaired arterial baroreflex inhibition of SNS tone: 3) impaired cardiopulmonary baroreflex inhibition of SNS tone; and 4) impaired integrative baroreflex inhibition of SNS tone. Specific Aim 5 will be to determine if a program of regular endurance exercise increases MSNA at rest in older adults, and whether the increase in MSNA is associated with an elevation in resting metabolic rate (RMR). We hypothesize that each of the mechanisms described in Specific Aims 1-4 will be associated with the age-related increases in MSNA and cardiac and total PNE spillover rates. We also hypothesize that in sedentary older adults, regular endurance exercise will result in an elevation in MSNA under resting conditions, and that this increase in MSNA will be associated with an elevation in RMR. As in the previous award, to test these hypotheses experiments will be performed using state-of-the art neurophysiological (Dr. Seals' laboratory) and neurochemical (Dr. Esler's laboratory) approaches for the study of both regional (skeletal muscle and heart) and whole-body SNS behavior. Healthy men and women over the adult age range with similar physical activity levels will be studied to determine the influence of the aging process per se on SNS activity (i.e., as opposed to disease, physical inactivity, etc.,). The results of these studies will extend considerably the findings from the previous award in providing new physiologically and clinically significant information on SNS activity and human aging. Such insight is important in light of the critical role of the SNS in the cellular regulation of tissue and organ function, much of which changes with aging. Moreover, this information is crucial considering the growing recognition that SNS pathophysiology may be a causal factor in a number of cardiovascular (essential hypertension; heart failure; coronary artery disease; ventricular arrhythmias) and metabolic (obesity; non-insulin dependent diabetes mellitus disease states all of which become more prevalent with advancing age.